While autism spectrum disorders (ASD) are highly heritable, it is clear that there is also a strong environmentalcomponent to ASD pathogenesis. ASD is frequently associated with brain enlargement, which is often presentat birth and affects multiple cell types, suggesting that dysfunction in an early stem or progenitor populationcontributes to ASD etiology. We hypothesize that brain enlargement is related to enhanced self-renewal ofneural stem cells (NSCs) leading in turn to increased neurogenesis and abnormal connectivity that has beenobserved in ASD. Mutations in the tumor suppressor PTEN that are observed in association with the autismmacrocephaly phenotype are almost all heterozygous (HET), although HET mutations in mice produce few orsubtle brain abnormalities. PTEN HET mutations in humans may or may not contribute to autism with brainovergrowth on their own but could act as a genetic susceptibility in combination with environmental factors thataffect their function. One known environmental risk factor for ASD that might interact with genetic risk factors isthe Maternal Inflammatory Response (MIR). Although MIR has been linked to both autism and to brainovergrowth, the biologic mechanisms for its potential pathological effects remain undefined. We will test thehypothesis that reactive oxygen species (ROS) generated by MIR exposure can increase stem cell self-renewal and neurogenesis in human neural stem cells through the reversible oxidative inactivation of PTENprotein and subsequent enhancement of PI3K pathway activation and that this effect is enhanced byheterozygous PTEN mutation. To do this we will use state of the art methods to generate lymphocyte-derivedinduced pluripotent stem cells (iPSCs) from our unique clinical population with identified PTEN HET mutations,brain overgrowth, and autism and from unaffected relatives. We will then derive forebrain NSCs from theiPSCs to test the hypothesis that PTEN mutations interact with ROS to promote an abnormal degree of self-renewing proliferation and neurogenesis. This will be done by directly exposing cells to ROS as well as tocandidate inflammatory cytokines that are known to be produced by MIR, and, which, in turn could activateROS production. We will determine the molecular mechanisms underlying the altered cellular phenotypes thatwe may observe through the analysis of the PI3K and other pathways that may interact with the PI3K pathway.We will also determine whether different forms of PTEN HET mutations which may result in different levels ofresidual PTEN function respond differently to ROS/cytokine stimulation. These studies will elucidate therelationship between genetic susceptibility and exposure to MIR that could inform the development of novelinterventions by identifying mechanisms of susceptibility to a common environmental risk factor. The findingsobtained in this study will also have broader implications for susceptibility to environmental autism risk factorsdue to the fact that there are many different genetic susceptibilities that may interact with MIR through finalcommon pathways which lead to altered neural stem cell function during critical periods in brain development..
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
